CCR5 drives glucose metabolic reprogramming to control microglial synaptic pruning via histone lactylation in a mouse model of depression.

SIK2-P300 axis Orchestrates the metabolic reprogramming and Immunological functions in microglia of Alzheimer's disease mice via a dual modulation of lactylation and Acetylation: An epigenetic Perspective.

Metabolic dysfunction in microglia is increasingly recognized as a core driver of Alzheimer's disease (AD) pathogenesis, and yet the underlying mechanisms remain elusive. Here, we identified salt-inducible kinase 2 (SIK2) as a critical metabolic checkpoint that was downregulated in microglia across the AD mouse models (5 × FAD, APP/PS1, and SAMP8). We found that a loss of SIK2 in microglia induced a pro‑inflammatory phenotype, thus impairing amyloid β-protein (Aβ) phagocytosis and rewiring glucose and lipid metabolism toward enhanced glycolysis and lipid accumulation. Mechanistically, SIK2 directly interacted with the histone acetyltransferase P300; SIK2 deficiency increased the activity of P300, elevating H3K9 acetylation and H4K8/12 lactylation at promoters of metabolic genes. The microglia‑specific SIK2 overexpression in the 5 × FAD mice mitigated cognitive deficits, Aβ pathology, neuroinflammation, and aberrant histone modifications. A pharmacological inhibition of P300 regained these protective effects. Our findings highlight the SIK2-P300 epigenetic axis as a key regulator of the metabolic homeostasis in microglia and a potential therapeutic target for AD treatments.

PLIN2-PGAM5-regulated lipid droplet-mitochondria contacts drive microglial neuroinflammation after spinal cord injury via fatty acid metabolic reprogramming.

Ischemia-induced p300-dependent histone lactylation activates an AP-1-SPP1 program in microglia to exacerbate ischemic brain injury.

Cerebral ischemia causes profound metabolic disruption, but how ischemia-associated metabolites reshape microglial chromatin and inflammatory function remains unclear. Here we identify histone lactylation as an epigenetic mechanism linking ischemic metabolic stress to pathogenic microglial activation. In transient middle cerebral artery occlusion mice and oxygen-glucose deprivation/reperfusion models, ischemic stress robustly increased H3K18la and H4K12la in microglia. CUT&Tag profiling showed widespread remodeling of both lactylation landscapes, with gained peaks preferentially associated with inflammatory, chemotactic, migratory and efferocytic programs. Integration with microglial RNA sequencing identified a concordantly activated gene network enriched for TNF, NF-κB, IL-17 and cytoskeletal regulatory pathways, with Spp1 emerging as a prominent effector linked to ischemia-induced lactylation. Motif enrichment and locus-level analyses implicated AP-1-associated regulatory elements, and ChIP-qPCR confirmed increased H3K18la and H4K12la at Fos and Spp1 regulatory regions after ischemia-like stress. Mechanistically, p300 depletion or inhibition reduced H3K18la/H4K12la accumulation, impaired AP-1-associated promoter engagement, and suppressed Fos, Spp1 and chemokine induction. Non-lactylatable H3K18R and H4K12R mutants attenuated Fos-Spp1 transcription and microglial migration, supporting cooperative regulation by these two marks. Functionally, microglia-specific Spp1 deletion reduced inflammatory microglial activation, neuronal apoptosis and long-term neurological deficits after ischemic injury. Pharmacological inhibition of p300 or AP-1, and SPP1 neutralization, similarly limited neuroinflammation and improved sensorimotor and cognitive recovery. Together, our findings define a lactate-p300-AP-1-SPP1 axis that couples ischemic metabolism to microglial chromatin remodeling and post-stroke neuroinflammatory injury.

From metabolism to neurodegeneration: how microglial functional reprogramming drives neurodegenerative diseases

Microglia are brain-resident myeloid cells that maintain central nervous system homeostasis and respond dynamically to neuronal injury, protein aggregation, and alterations in the local metabolic environment. Single-cell and single-nucleus studies demonstrate that microglial responses in neurodegenerative diseases are highly heterogeneous and cannot be adequately explained by the classical M1/M2 polarization model. Increasing evidence further indicates that metabolic remodeling is not merely a consequence of activation but a determinant of microglial migration, phagocytosis, inflammatory signaling, redox balance, organelle function, and interactions with surrounding neural cells. In this review, we propose a microglial immunometabolic trajectory framework in which metabolic states are viewed as branching and potentially reversible determinants of cellular function rather than fixed stages of a universal disease pathway. We summarize how glucose metabolism, mitochondrial function, lipid metabolism, amino acid metabolism, lysosomal activity, and redox regulation shape microglial plasticity. We further examine relationships among transcriptionally defined states, including disease-associated microglia, microglia associated with neurodegeneration, lipid-droplet-accumulating microglia, and other disease-enriched populations, while emphasizing that transcriptional similarity does not necessarily imply metabolic function or lineage progression. Comparative evidence from Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis indicates that common metabolic regulators, including HIF-1α, mTOR, PKM2, TREM2, APOE, and NLRP3, exert disease-specific effects with unequal mechanistic support. We further distinguish associative metabolic signatures from intervention-based causal evidence and discuss limitations of animal models, immortalized cell lines, postmortem tissue, and induced pluripotent stem cell-derived microglia. Finally, we highlight the need for cell-specific, state-resolved, and temporally precise metabolic interventions that restore defined microglial functions without compromising physiological immune surveillance.

Glycogen-Dependent Metabolic Reprogramming Regulates Microglial Activation and Dysfunction in Neurodegenerative Disease

Microglia are central regulators of neuroinflammation in Alzheimer’s disease (AD), yet how metabolic states modulate function remains unclear. Here we show that microglia from the APPNL-G-F mouse model revealed upregulation of glycolytic enzymes coinciding with onset of microglial activation. Surprisingly, this glycolytic shift occurred alongside reduced expression of glucose transporters, suggesting that extracellular glucose may not be the primary fuel source, implicating glycogenolysis as the potential metabolic driver. Consistent with this, significant microglial glycogen accumulation was noted in late disease, when cells exhibited features of metabolic exhaustion and functional impairment. Pharmacological inhibition of glycogenolysis blunted microglia responses to Abeta aggregates and markedly reduced Abeta uptake, confirming a functional role for glycogen metabolism in shaping microglial states. Together, these findings identify glycogen as a central regulator of microglial metabolic health and function, highlighting glycogen homeostasis as a potential therapeutic target for promoting Abeta clearance and preserving protective microglial functions in AD.

Microglial Deubiquitinase OTUD7B Stabilizes STAT3 to Promote Neuroinflammation and Cognitive Decline in Alzheimer's Disease

ABSTRACT Neuroinflammation driven by microglial activation is a defining feature of Alzheimer's disease (AD), yet the molecular mechanisms sustaining this proinflammatory state remain unclear. Here, we identify the deubiquitinase OTUD7B as a critical regulator of microglial activation and AD pathology. OTUD7B expression was markedly elevated in microglia from AD mouse models and human patient datasets. Genetic ablation of OTUD7B markedly attenuated microglial activation and cytokine release, alleviated neuronal injury, and improved cognitive performance in AD mice. Mechanistically, OTUD7B directly interacted with STAT3 and removed K48‐linked ubiquitin chains at lysine 283, thereby stabilizing STAT3, promoting its nuclear translocation, and enhancing transcription of proinflammatory mediators. Integrative transcriptomic analysis revealed that OTUD7B deficiency suppressed proinflammatory transcriptional programs in microglia. Together, these findings uncover an OTUD7B‐STAT3 signaling axis that sustains microglial‐driven neuroinflammation and identify OTUD7B as a potential therapeutic target for mitigating neurodegenerative pathology in AD.